DESCRIPTION: (Applicant's Abstract) Previous studies found that hypertensive SHR rats showed smaller pain responses in acute pain models and suggested that blood pressure control systems can attenuate the processing of brief nociceptive signals. By contrast, preliminary studies found that SHR rats show exaggerated nociceptive responses in a model of inflammatory pain (the formalin test). To test the hypothesis that hypertension decreases nociception in tests of acute pain, and increases nociception in tests of persistent pain, AIM 1A will evaluate nociceptive responses in awake, unrestrained rats in two acute models of nociception and in the formalin test (a short-duration model of persistent inflammatory pain) after: 1) Reduction of blood pressure in SHR rats; and 2) Increases of blood pressure in normotensive rats. Whereas inflammatory pain in the formalin test lasts one hour, inflammatory pain in an arthritic model and neuropathic pain in a spinal nerve ligation model is manifested by hyperalgesia that lasts days to weeks. AIM 1B will evaluate nociception in these models using SHR rats and other experimental models of hypertension. Naloxone eliminates the difference in acute pain sensitivity between normotensive and SHR rats, indicating that tonic endogenous opioid activity is greater in the SHR rat. To test the hypothesis that opioids regulate inflammatory hyperalgesia in the hypertensive rat, AIM 2 will evaluate the effects of selective opioid receptor agonists and antagonists on persistent pain in the SHR rat and other experimental models of hypertension. Sympathetic activity is a crucial determinant of blood pressure, and may also exacerbate the inflammatory hyperalgesia associated with tissue injury. Based on preliminary results obtained with a short-acting opioid agonist, it was concluded that peripheral mechanisms during acute nociception modulate the temporal profile of persistent nociception. To test the hypothesis that hypertension contributes to the magnitude and temporal profile of inflammation, AIM 3A will evaluate the effects of opioids on plasma extravasation and prostaglandin content in multiple models of hypertension. Nociception and cardiovascular systems are also controlled by supraspinal sites, notably the noradrenergic locus coeruleus (LC). Since activity of the LC is depressed in the SHR rat and since activation of the LC is antinociceptive, the exaggerated nociceptive responses in the SHR may reflect abnormal functioning of the LC. To test this hypothesis, AIM 3B will use a novel neurotoxin to selectively lesion the noradrenergic neurons of the LC, followed by evaluation of arterial pressure and nociception. The results of these studies will facilitate our understanding of the mechanisms that contribute to chronic pain in the hypertensive patient.